(Topics in heterocyclic chemistry 8) kiyoshi matsumoto (auth ), shoji eguchi (eds ) bioactive heterocycles II springer verlag berlin heidelberg (2007)

As part of the series Topics in Heterocyclic Chemistry, this volume titled Bioac-tive Heterocycles II presents comprehensive and up-to-date reviews on selected topics regarding syntheti

Topics in Heterocyclic Chemistry Series Editor: R R Gupta

Editorial Board:

D Enders · S V Ley · G Mehta · A I Meyers

K C Nicolaou · R Noyori · L E Overman · A Padwa

Topics in Heterocyclic Chemistry

Series Editor: R R Gupta

Recently Published and Forthcoming Volumes

Bioactive Heterocycles III

Volume Editor: M T H Khan

Volume 9, 2007

Bioactive Heterocycles II

Volume Editor: S Eguchi

Volume 8, 2007

Heterocycles from Carbohydrate Precursors

Volume Editor: E S H El Ashry

Volume 7, 2007

Bioactive Heterocycles I

Volume Editor: S Eguchi

Volume 6, 2006

Marine Natural Products

Volume Editor: H Kiyota Volume 5, 2006

QSAR and Molecular Modeling Studies

Heterocyclic Antitumor Antibiotics

Volume Editor: M Lee Volume 2, 2006

Microwave-Assisted Synthesis of Heterocycles

Volume Editors: E Van der Eycken, C O Kappe Volume 1, 2006

Bioactive Heterocycles II

Volume Editor: Shoji Eguchi

With contributions by

M Ariga · H Fujii · A B Hendrich · H Ichinose · K Matsumoto

K Michalak · N Motohashi · S Murata · H Nagase · N Nishiwaki

N Shibata · T Toru · F Urano · O Wesołowska

T Yamamoto · M Yamashita

123

The series Topics in Heterocyclic Chemistry presents critical reviews on “Heterocyclic Compounds”

within topic-related volumes dealing with all aspects such as synthesis, reaction mechanisms, structure complexity, properties, reactivity, stability, fundamental and theoretical studies, biology, biomedical studies, pharmacological aspects, applications in material sciences, etc Metabolism will be also in- cluded which will provide information useful in designing pharmacologically active agents Pathways involving destruction of heterocyclic rings will also be dealt with so that synthesis of specifically functionalized non-heterocyclic molecules can be designed.

The overall scope is to cover topics dealing with most of the areas of current trends in heterocyclic chemistry which will suit to a larger heterocyclic community.

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As part of the series Topics in Heterocyclic Chemistry, this volume titled

Bioac-tive Heterocycles II presents comprehensive and up-to-date reviews on selected

topics regarding synthetic as well as naturally occurring bioactive heterocycles.The first chapter, “High Pressure Synthesis of Heterocycles Related to Bioac-tive Molecules” by Kiyoshi Matsumoto, presents a unique high-pressure syn-thetic methodology in heterocyclic chemistry Basic principles and fruitfulexamples for pericyclic reactions, such as Diels-Alder reactions, 1,3-dipolarreactions, and also for ionic reactions, such as SN and addition reactions, arediscussed The review will be of considerable interest to heterocyclic chemistsand synthetic chemists

The second chapter, “Ring Transformation of Nitropyrimidinone Leading toVersatile Azaheterocyclic Compounds” by Nagatoshi Nishiwaki and MasahiroAriga, presents a very critical review on novel ring transformations of dini-tropyridones and nitropyrimidinones based on the work of his group Ad-dressed in this review is the synthesis of functionalized molecules, such asnitroanilines, nitropyridines, and nitrophenols, by the ring transformation ofdinitropyridones as the nitromalonaldehyde equivalent Ring transformations

of nitropyrimidinones with dinucleophiles to 4-pyridones, pyrimidines and4-aminopyridines, and to polyfunctinal pyridones with 1,3-dicarbonyl com-pounds, etc., are also discussed This review may attract the interest of syntheticchemists as well as heterocyclic chemists in the life science fields

The third chapter, “Synthesis of Thalidomide” by Norio Shibata, TakeshiYamamoto and Takeshi Toru, describes a modern synthetic aspect of thalido-mide

This drug has had a disastrous medical history due to its teratogenicity,however, its recently found efficacy toward so-called incurable diseases, such

as leprosy, AIDS, and various cancers, has revived researchers’ interest, inparticular for the production of optically pure isomers From this point ofview, this article may be attractive to medicinal and pharmaceutical chemists,and also heterocyclic and synthetic chemists

The fourth chapter, “Rational Drug Design of delta Opioid Receptor AgonistTAN-67 from delta Opioid Receptor Antagonist NTI” by Hiroshi Nagase andHideaki Fujii, presents the fascinating and successful drug design of deltaopioid receptor agonist TAN-67 from delta opioid receptor antagonist NTI

based on the work by Nagase and his coworkers The drug design requires

a high level of synthetic technology in order to provide designed molecules forpharmacological evaluations This article represents a very brilliant example

of molecular design and may attract much attention from researchers in thefields of pharmacology, medicinal chemistry, and organic synthesis

The fifth chapter, “Tetrahydrobiopterin and Related Biologically ImportantPterins” by Shizuaki Murata, Hiroshi Ichinose and Fumi Urano, describes

a modern aspect of pteridine chemistry and biochemistry Pteridine derivativesplay a very important role in the biosynthesis of amino acids, nucleic acids,neurotransmitters and nitrogenmonooxides, and metabolism of purine andaromatic amino acids Some pteridines are used in chemotherapy and for thediagnosis of various diseases From these points of view, this article will attractconsiderable attention from medicinal and pharmaceutical chemists, and alsoheterocyclic chemists and biochemists

The sixth chapter, “Preparation, Structure and Biological Property of phorus Heterocycles with a C-P Ring System” by Mitsuji Yamashita presents

Phos-a very criticPhos-al review of novel phosphorus heterocycles The review discussesaliphatic 4-, 5-, 6- and 7-membered C-P-C heterocycles, aromatic C-P-C het-erocycles, and various C-P-O type heterocycles including phospha sugars.Synthetic aspects, structural studies, and the biological properties of thesephosphorus heterocycles are also addressed This chapter may attract the in-terest of synthetic chemists as well as heterocyclic and heteroatom chemists inthe life science fields

The final chapter, “The Role of the Membrane Actions of Phenothiazinesand Flavonoids as Functional Modulators” by K Michalak, O Wesolowska,

N Motohashi and A B Hendrich, presents a very comprehensive review on portant biological effects of phenothiazines and flavonoids due to interactionswith membrane proteins and the lipid phase of membranes The discussionincludes the influence of these heterocycles on model and natural membranes,modulation of MDR transporters by these heterocycles, and the effects of theseheterocycles on ion channel properties This review may attract much interestfrom medicinal and pharmaceutical chemists as well as heterocyclic chemists

im-in the life science fields

I hope that our readers find this series to be a useful guide to modern rocyclic chemistry As always, I encourage both suggestions for improvementand ideas for review topics

High-Pressure Synthesis of Heterocycles

Related to Bioactive Molecules

K Matsumoto 1

Ring Transformation of Nitropyrimidinone

Leading to Versatile Azaheterocyclic Compounds

N Nishiwaki · M Ariga 43

Synthesis of Thalidomide

N Shibata · T Yamamoto · T Toru 73

Rational Drug Design ofδ Opioid Receptor Agonist TAN-67

fromδ Opioid Receptor Antagonist NTI

H Nagase · H Fujii 99

Tetrahydrobiopterin and Related Biologically Important Pterins

S Murata · H Ichinose · F Urano 127

Preparation, Structure, and Biological Properties

of Phosphorus Heterocycles with a C–P Ring System

M Yamashita 173

The Role of the Membrane Actions of Phenothiazines

and Flavonoids as Functional Modulators

K Michalak · O Wesołowska · N Motohashi · A B Hendrich 223

Author Index Volumes 1–8 303

Subject Index 307

Bioactive Heterocycles I

Volume Editor: Eguchi, S.

ISBN: 978-3-540-33350-0

Directed Synthesis of Biologically Interesting Heterocycles

with Squaric Acid (3,4-Dihydroxy-3-cyclobutene-1,2-dione)

Based Technology

M Ohno · S Eguchi

Manganese(III)-Based Peroxidation of Alkenes to Heterocycles

H Nishino

A Frontier in Indole Chemistry:

1-Hydroxyindoles, 1-Hydroxytryptamines, and 1-Hydroxytryptophans

Top Heterocycl Chem (2007) 8: 1–42

DOI 10.1007/7081_2007_058

© Springer-Verlag Berlin Heidelberg

Published online: 23 June 2007

High-Pressure Synthesis of Heterocycles

Related to Bioactive Molecules

Kiyoshi Matsumoto

Department of Pharmaceutical Sciences, Faculty of Pharmacy,

Chiba Institute of Science, Choshi, 288-0025 Chiba, Japan

kmatsumoto@cis.ac.jp

1 Introduction 3

1.1 A Short Note on High-Pressure Chemistry 3

1.2 Basic Principles 4

1.3 Effects of Pressure on Various Properties of Solvents 6

1.4 High-Pressure Apparatus and Experimental Procedures 6

2 Pericyclic Reactions 9

2.1 Intermolecular Diels–Alder Reactions 10

2.2 Intramolecular Diels–Alder Reactions 23

2.3 1,3-Diploar Reactions 27

2.4 Other Pericyclic Reactions 31

2.4.1 [2 + 2] Cycloadditions 31

2.4.2 [2 + 2 + 2] Cycloadditions 32

2.4.3 Multicomponent Cycloadditions (MCCs) 33

3 Ionic Reactions 34

3.1 SN Reactions 34

3.2 Addition Reactions 36

3.3 Other Ionic Reactions 37

4 Concluding Remarks 38

References 39

Abstract The present article describes 1) how to perform high-pressure experiments; and 2) the most recent examples of synthetic applications of high-pressure mediated per-icyclic reactions, such as inter- and intramolecular Diels–Alder reactions, 1,3-dipolar reactions, and multicomponent cycloadditions to heterocycles related to biologically in-teresting molecules The article also extends to ionic reactions in a similar fashion, though not many examples have been investigated The scope and limitations are also described when necessary.

Keywords Addition reaction · 1,3-Dipolar reaction · Diels–Alder reaction ·

High pressure · Substitution reaction

Abbreviations

AcOEt Ethyl acetate

HMPA Hexamethylphosphoric triamide

IEDAR Intermolecular Diels–Alder reaction

IRDAR Intramolecular Diels–Alder reaction

MATBr Methylaluminum bis(2,4,6-tribromophenoxide)

Pet Et Petroleum ether

PTFE Polytetrafluoroethylene (Teflon®)

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 3

1

Introduction

1.1

A Short Note on High-Pressure Chemistry

High pressure is encountered in the deep sea, inside the earth, and on otherplanets High pressure is likely to have been an agent in the geochemicalconditions that formed coal and oil deposits [1] Even more, biological andphysicochemical arguments in support of a high-pressure origin for life onEarth have been recently reviewed [2] It is interesting to research the change

of molecules at high pressure because the pressure affects molecular ronments When covalent bond formation takes place, the model is simplyassumed that one molecule collides with another molecule But it has beenclarified that solvent, concentration, temperature, and pressure around themolecules actually affect the reaction The use of extreme conditions such

envi-as ultrahigh pressure in materials science and industry led to the ful preparation of synthetic diamond, ruby, and borazone as early as the1950s [3, 4] Around 1980, high-pressure apparatus, such as autoclave appa-ratus, became popular But until then the utility of high pressure in organicsynthesis had not been widely explored in spite of its potential Of the manyparameters that could be changed to improve the results of synthetic trans-formation, much attention has been paid to the study of electronic andsteric effects by chemical modification of substrates and reagents, to ther-mal and photochemical effects, to the use of catalysts such as Lewis acids andbases, and to phase-transfer reagents Sonochemistry, flash vacuum pyrol-ysis and other thermal processes, electroorganic transformations, reactionswith solid-supported reagents and catalysts [5], and solvent-free organic syn-thesis [6] have also been employed Supercritical fluids have also been used,and this can often be an alternative to the use of organic solvents under highpressure [7] In particular, microwave techniques [8] are now quite popularbecause of the wide availability as well as quite easy operation, and even anordinary microwave oven being successfully used

success-Interest has been generated in the high-pressure method since it wasdemonstrated that high pressure is not only useful in effecting cycloaddi-tion reactions, but also several kinds of ionic reactions [9–16] The aim ofthe present article is to review recent examples of the use of high pressurefor the synthesis of heterocycles related to biologically interesting molecules,and to predict some further possibilities The present review covers eitherrepresentative or most recent examples

Basic Principles

At present, most methods of organic synthesis are based on chemical cation of reagents and catalysts Nevertheless, frequent use has recently beenmade of “distinctive” techniques, such as ultrasound, flash vacuum pyroly-sis, electroorganic, microwave, supercritical, solvent-free (or otherwise solidsate), and even plasma conditions, for syntheses of organic materials Thehigh-pressure technique is one of the most developed nonconventional toolsfor the preparation of either new or known compounds Chemical reactions

modifi-at high pressure require conditions characterized by high number densities

of the reacting particles Thus, considerable degrees of intense cular interactions take place depending on the applied pressures In terms

intermole-of the potential energy intermole-of interactions as a function intermole-of the distance betweenmolecules or atoms, the repulsive part of the relationship is mainly discussed

At lower number densities, interactions of this type take place only at highertemperature, but within a limited time interval determined by the impactparameters At higher pressure, the duration of these strong interactions ismuch longer This phenomenon may lead to a considerable increase in thereaction rates (Fig 1)

In principle, the fundamental equation for the effect of high pressure on

a reaction rate constant was deduced by Evans and Polanyi on the basis oftransition state theory:

where∆V= |(= V= |– VR) is called the volume of activation and is the difference

between the volume (V=|) of the activated complex, including molecule(s)

of the solvation shell, and the volume (VR) of the reactant molecule(s) sociated with the solvent molecule(s), measured at constant pressure andtemperature

as-In general, formation of a bond, concentration of charge, and ionizationduring the transition state lead to a negative volume of activation, whereas

Fig 1 High-pressure effects on organic reactions

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 5cleavage of a bond, dispersal of charge, neutralization of the transition state,and diffusion control lead to a positive volume of activation For reactions inwhich the polarity of the transition state changes, the influence of the solvent

on∆V= | is of importance Thus, the types of organic reactions in which rate

enhancement is expected on application of pressure may be summarized, as

a preparative or synthetic guide, as follows:

1 Reactions in which molecularity decreases in the products; e.g., ditions, condensations

cycload-2 Reactions which proceed via cyclic transition states; e.g., Claisen and Coperearrangements

3 Reactions which take place through dipolar transition states; e.g., schutkin reactions, electrophilic aromatic substitution

Men-4 Reactions that do not take place or otherwise occur in low yields due tosteric hindrance in transition states

As described above, the activation volume is the difference in partial molarvolume between the transition state and the initial state From a syntheticpoint of view this could often be approximated by the difference in the mo-lar volume between the reactant(s) and product(s) Partial molar activationvolumes, which can be divided into a structural part and a solvent-dependentpart, are of considerable value in speculating about the nature of the tran-sition state This thermodynamic property has led to many studies on themechanism of organic reactions

From Eq 1, the application of pressure accelerates reactions which have

a negative volume of activation The system does not strictly obey the idealrate equation above ∼ 1.0 GPa since the activation volume is itself pres-sure dependent; the values of ∆V= | generally decrease as pressure increases.

Innumerable data on∆V= | are now available If the∆V= | value is not

avail-able for a reaction type of interest, ∆S= | data may serve as a guide

In-deed, a linear relationship of∆V= | with∆S= | has been reported for a variety

mech-as kg m s–2 The SI unit of pressure is one Newton per square meter (N m–2)which is called a Pascal (Pa); 1 bar = 105Pa; thus, the Pa is used in this chapter

as an approximate equivalent to other units (Table 1)

Table 1 The units of pressure

Effects of Pressure on Various Properties of Solvents

Before performing high-pressure experiments, it is essential to have ledge of the effects of pressure on various physical properties of the solvent,such as freezing temperature, density, viscosity, solubility, compressibility, di-electric constant, and conductivity, although unfortunately sufficient data onall these properties are often unavailable The less polar solvents have highercompressibilities and are therefore more constricted by ionic or dipolar so-lutes than the more polar solvents, which exhibit smaller compressibilitiesowing to the strong intermolecular interactions

know-The melting point of liquids is raised by increasing the pressure; this effectamounts to∼ 15–20◦C per 100 MPa Tables 2 and 3 summarize the freez-

ing temperatures [3] and the viscosity of common solvents at high pressure,respectively [14]

The solubility of solids in liquids often decreases as the pressure is raised,the reagents often crystallizing out from the solvents The viscosity of liquidsincreases by approximately two times every 100 MPa, thus diffusion control ofthe reaction is important

1.4

High-Pressure Apparatus and Experimental Procedures

This review gives only a brief account of the equipment used in high-pressureorganic synthesis [14, 16] The most general and convenient method for ob-taining high pressures is disproportion, i.e., application of Pascal’s principle.Particularly in organic synthesis, a piston–cylinder device may be most satis-factory A maximum pressure of ca 5.0 GPa is obtainable with such a devicewhen constructed of cemented tungsten carbide Although miscellaneoustypes of piston and cylinder apparatus have been devised, depending on thepurpose of the experiments, they consist essentially of a high-pressure vessel,

a pressure gauge (usually Bourdon or manganin or strain gauges), a pump,

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 7

Table 2 Freezing temperatures of common solvents at high pressure

up to ca 60◦C, several kinds of commercially available syringes and

polyethy-lene tubes have also been used

Table 3 Ratio of viscosity at pressure P and 0.1 MPa ( ηp/η1 ) of common solvents

double-High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 9

Fig 3 Examples of flexible sample containers used at high pressures

In most preparative experiments under high pressure, the procedure is

as follows: pressure is applied at room temperature (rt) to a sample tubecontaining the reagents and, if necessary, catalysts and solvent, before thetemperature is raised, if required After a suitable time, the heater is switchedoff After cooling to rt, the pressure is carefully released, and the sample tube

is removed from the vessel When the reaction at high pressure does not takeplace at ambient temperature, according to GC, TLC, NMR, or other analyti-cal techniques, an increase of pressure and/or temperature might be effective

In certain cases, the use of a catalyst may lead to success

2

Pericyclic Reactions

Of the wide variety of pericyclic reactions, cycloadditions have been mostextensively studied both for mechanistic and synthetic aspects Cycload-dition reactions have been defined, classified, and reviewed in two fash-ions [17, 18] Cycloadditions can be facilitated under a variety of condi-tions, such as addition of catalysts, application of high-temperature orhigh-pressure conditions, or use of microwave techniques, etc As a re-sult, the conditions of cycloaddition reactions can usually be selected insuch a way as to accommodate sensitive functionality in the substrate

An application of the high-pressure technique to this type of reaction isanticipated to be extremely fruitful on both kinetic (∆V= |< 0) and thermo-

dynamic (∆V < 0) grounds Indeed, activation volumes of cycloadditionsrange from – 7 to – 50 cm3mol–1 It is noteworthy that high-pressure con-ditions often improve the yield of cycloadditions and, in some cases, affordthe opposite configuration of the cycloadducts compared with conventionalmethods [19–21]

Intermolecular Diels–Alder Reactions

Since Diels and Alder discovered nearly 75 years ago the formation of a 1 : 1adduct in the reaction of cyclopentadiene with 1,4-benzoquinone, the Diels–Alder reaction, the prototype of [4 + 2] cycloadditions, has become indis-pensable to synthetic chemists and has the advantages of excellent stere-

ospecificity, predictable endo stereoselectivity, and regioselectivity

Further-more, it serves as an indirect and general method for the introduction and/orconversion of functional groups, through suitable bond-breaking reactions of

an initially formed adduct Intermolecular Diels–Alder reactions (IEDARs)exhibit a large negative volume of activation (ca – 25 to – 45 cm3/mol),

together with a large negative volume of reaction Among high-pressure diated reactions, preparative IEDARs have been most extensively explored

me-As one of the key steps toward manzamine B, the reaction of done with Danishefsky’s diene was performed At a high pressure of 1.5 GPa,

dihydropyri-the reaction proceeded cleanly to give 66% yield of dihydropyri-the adduct 1, whereas

under thermal conditions (in p-cymene at 200–220◦C, 18 h) 1 was produced

in 53% yield (Scheme 1) [22]

Scheme 1 IEDAR of dihydropyridone with Danishefsky’s diene [22]

Porphyrins and their synthetic analogues have been extensively tigated because of their increasingly diverse applications in fields rangingfrom catalysis to biomedical science One of the most general and simplestmethods for modification of the porphyrin core would be attachment of ad-ditional moieties by the IEDAR of vinyl porphyrins with electron-deficientdienophiles However, the dienophiles so far used are limited to highly ac-tive ones, such as tetracyanoethylene (TCNE) and dimethyl acetylenedicar-boxylate; the generality of this method has not been demonstrated Ni(II)

inves-β-vinyl-meso-tetraphenylporphyrin (2) undergoes IEDAR with such usual

dienophiles as N-aryl and N-alkyl maleimides, dimethyl fumarate, dimethyl

maleate, and methyl acrylates to give the six-membered condensed phyrins which form from the IEDA adducts, followed by 1,3-hydrogen shifts

por-as illustrated in Scheme 2 The yields of the adducts were highly improved byapplied pressure [23, 24]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 11

Scheme 2 IEDAR of Ni(II)β-vinyl-meso-tetraphenylporphyrin (2) [23, 24]

Numerous Amaryllidaceae alkaloids include phenanthridine skeletons,one of whose constructive methods constitutes an IEDA strategy In somecases, the functionality on the dienophile influences the stereochemistry ofcycloaddition reactions under high-pressure conditions For example, the re-

actions of (E)-buta-1,3-dienyl acetate (6) and the quinolin-2(1H)-ones 7 gave

rise to different configurations in the products 8 and 9, depending on the functional groups at the 4-position of 7 (Scheme 3) These results reflect

Scheme 3 Reactions of (E)-buta-1,3-dienyl acetate (6) with 2(1H)-quinolones 7 [25]

different activation energies (Ea) for the endo and exo adducts 8 and 9,

re-spectively For R = COOH, the calculated Eavalues for endo vs exo addition

to 8a and 9a, respectively, were reported as 33.5 vs 34.2 kcal/mol In the case

of R = CN, the corresponding values for 8b and 9b were 36.9 vs 35.9 kcal/mol,

respectively, indicating that the pathway with the smaller activation volumewas preferred under high-pressure conditions [25] Analogous IEDARs werealso reported [26]

Madangamine A (10) is a pentacyclic alkaloid produced by marine sponge

Xestospongia ingens This compound is of interest both because of its unique

structure and the fact that it shows significant in vitro cytotoxic activity ward a number of tumor cell lines, including human lung A549, brain U373,

to-and breast MCF-7 A concise approach to the tricyclic core 11 of 10 was

achieved in terms of high-pressure IEDARs (Scheme 4) [27] This reactionwas unsuccessful under thermal conditions

Scheme 4 Construction of tricyclic core 11 via IEDAR [27]

Indoles often serve as dienophiles whose IEDARs lead to containing polycycles useful in the synthesis of biologically active alkaloids

nitrogen-A recent example for the combination of Lewis acid catalyst and high

pres-sure is the reaction of 2,3-dimethylbuta-1,3-diene (12) with the indole 13 As shown in Scheme 5, quantitative yields of the adducts 14 and 15 were ob-

tained under high-pressure conditions Interestingly, the combination of highpressure and ZnCl2 as catalyst afforded mainly the opposite configuration

in 15 [28] It is worth noting that all-carbon IEDARs are kinetically favored,

which is in accord with the observed higher reactivity of the aromatic C=C

bond relative to the (unaffected) formyl group in the indole, producing 14

exclusively (in the absence of catalyst) under high pressure Both SnCl4 and

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 13

Scheme 5 Effect of pressure and catalyst in the reaction of dimethylbutadiene (12) with the indole 13 [28]

ZnCl2accelerate the second IEDAR, in which the trans (e.g., 2
R) cycloadduct

was formed via an anti-type transition state under thermal conditions In contrast, at high pressure, the corresponding cis (e.g., 2
S) cycloadduct were

formed via a syn-type transition state, which has a smaller activation volume

(data not given)

Although the furan unit has become an important diene in the sis of natural products, 2-vinylfurans have been less exploited In certaincases, a high-pressure mediated IEDAR is useful for this type of furan For

synthe-example, the reaction of methyl 5-ethenyl-2-methylfuran-3-carboxylate (16)

Scheme 6 Reactions of methyl 5-ethenyl-2-methylfuran-3-carboxylate (16) with methyl acrylate (17) and dimethyl maleate 19 under thermal and high-pressure conditions [29]

and methyl acrylate (17) afforded the adduct 18, without concomitant

arom-atization, albeit in low yield (23%) [29] It is noted that, in the case of the

similar reaction between 16 and dimethyl maleate (19), the resulting adduct

underwent aromatization via C=C migration

As previously described, furans are one of most versatile starting rials for natural and bioactive molecules since the resulting adducts, 7-oxa-bicyclo[2.2.1]heptanes, are of highly practical importance as a variety offunctionalizations of the adducts are possible Because of the aromatic char-acter of furans, conventional IEDARs are often unsuccessful; thus, there aremany examples of IEDARs that were performed at high pressure [9–14].Therefore, this methodology is still employed by many research groups Forexample, in order to construct the CD ring of the anticancer agent paclitaxel

mate-(Taxol®), the reactions of several furans 20 with citraconic anhydride (21) were preliminarily studied under high pressure Furan (20: R = H) with citra-

conic anhydride (21) afforded the exo adduct 22 (R = H) diastereoselectively, whereas 2-substituted furans 20 gave an approximately 1 : 1 mixture of exo

regioisomers 22 and 23 [30].

Scheme 7 IEDARs of furans 20 with citraconic anhydride 21 [30]

Cantharidin (24) [31] represents the simplest known inhibitor of the

ser-ine/threonine protein phosphatases 1 and 2A, and can be isolated from dried

beetles (Cantharis vesycatoria) The simplest synthesis of 24 from furan and

dimethylmaleic anhydride met with failure, even at pressures as high as6.0GPa either at rt or at temperatures of up to 350◦C, presumably due to

the thermodynamic instability of the adduct at normal pressure, e.g., whenpressure is released [32] However, if this reaction could be carried out inthe presence of Pd/C and H2, 24 might be obtained in one step Nevertheless,

high-pressure cycloaddition turned out to be very useful for the sis of cantharidin and its derivatives [31–33] For instance, (±)-palasonin

synthe-was synthesized from furan and citraconic anhydride (21) at 0.8 GPa for

138h, followed by hydrogenation over Pd/C Neither high temperatures nor

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 15

Scheme 8 A simple synthesis of cantharidin analogues [33, 34]

Grieco conditions (LiClO4, Et2O, H2O) are effective in this transformation

at atmospheric pressure The two cantharidin analogues 25 displaying PP1

selectivity were obtained by high-pressure IEDARs of furan and thiophene

with dimethyl maleate (Scheme 8) They possess PP1 selectivity (> 40- and

> 30-fold selectivity) over PP2A Both 25a and 25b exhibited a moderate PP1

activity with IC50values of 50 and 12.5µM, respectively; however, the

corres-ponding monoester of 25a showed no such selectivity [34] Similarly, simple and alkyl-substituted cycloalkenones such as 26 undergo IEDARs with sul- fanylfuran 27 and, to a lesser extent, with 3-phenylsulfanylfuran 28 to afford

the adducts, albeit in poor yields (Scheme 9) [35]

Scheme 9 IEDARs of sulfanylfurans 27 and 28 with cycloalkenones 26 [35]

Pyrrole is believed to be more aromatic than furan, with an aromaticstabilization energy estimated to be 100–130 kJ mole–1, thus only with suchextremely powerful dienophiles as tetrakis(trifluoromethyl)Dewar thiophenewere the IEDA adducts isolated Therefore, several attempts to achieve anIEDAR with pyrroles using high pressure have been made [9–14].

Epibatidine (30), an alkaloid isolated from the skin of the Ecuadorian

poi-son frog Epipedobates tricolor, was reported as a novel, highly potent,

nono-pioid analgesic agent and a specific agonist of central nicotinic acetylcholine

receptors (nAChRs) The high-pressure IEDAR of N-methoxycarbonylpyrrole

(31) with phenyl vinyl sulfone produced a mixture of endo- and

exo-5-phenylsulfonyl-7-methoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (32), which was desulfonylated in the usual fashion to give 33, followed by reductive

Heck reactions and treatment with Me3SiI, affording epibatidine analogues(Scheme 10) [36]

Scheme 10 A facile synthesis of the intermediates of epibatidine analogues via

high-pressure IEDARs of pyrrole 31 [36]

It is known that thiophene (34) is more aromatic than pyrrole and

does not undergo IEDAR under conventional conditions However, almost

25 years ago, it was reported that the reaction with maleic anhydride (35)

at 1.2–2.0 GPa and a temperature of 100◦C produced the exo adduct 36 in

40% yield [37] Recently, highly improved results have been attained underhigh-pressure and solvent-free conditions (Scheme 11) [38]

2-Pyrones usually behave as aliphatic compounds, and therefore a ber of IEDARs were reported with both electron-deficient and electron-richdienophiles, but these adducts are prone to lose CO2under conventional con-ditions Thus, a number of examples that retain the useful CO2 moiety haveappeared via recourse to high-pressure strategy [9–14]

num-High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 17

Scheme 11 IEDAR of thiophene (34) with maleic anhydride (35) under high-pressure/

solvent-free conditions [38]

The palmarumycins are a group of fungal metabolites isolated from

Co-niothyrium sp Specifically, palmarumycin CP1 (37) may be considered as

the parent member of this group, with others displaying a range of ylation, unsaturation, or epoxidation Several of them exhibit antibacterial,antifungal, or potentially anticancer activity One of the simplest approaches

hydrox-to the palmarumycin skelehydrox-ton would be IEDARs of 3-methoxy-2-pyrone (38) with benzoquinone monoacetals 39, as exemplified in Scheme 12 [39] How-

ever, in this case, no high-pressure conditions seem to be essential because ofthe need for aromatization Rather than high pressure, microwave irradiationmight be a method of choice

2-Pyridones are classified as aromatic heterocycles (estimated aromaticstabilization energy: about 100 kJ/mol) Indeed, they undergo electrophilic

Scheme 12 Synthetic approaches to the palmarumycins [39]

substitution at the 3- and 5-positions In connection with the strategic point for construction of the isoquinuclidine skeleton, their IEDARs are ofconsiderable interest 2-Pyridones are much more inert to dienophiles than2-pyrones, the initial adducts often losing an RHCO group under conven-tional conditions These difficulties are partly surmounted by recourse to

view-the high-pressure technique [9–14] Cyclooctyne (41) is view-the smallest cyclic

alkyne that is stable at rt In particular, its cycloadditions and subsequentring enlargement have been utilized for construction of medium- and large-

ring compounds [40] Some 2-pyridones 42 underwent high-pressure IEDARs with cyclooctyne (41) to give the corresponding stable bridged tricyclic adducts 43 in moderate to good yields (Scheme 13) [41].

Scheme 13 IEDARs of 2-pyridones 42 with cyclooctyne (41) at 0.8 GPa [41]

The IEDAR of tetramethyl-4H-pyrazole (44) with 2,5-dihydrofurans 45

was accomplished only by high pressure in the strict absence of any acid

traces, giving the adduct 46 in 74% yield Attempts to perform the reaction at

temperatures up to 150◦C by using microwave irradiation (700 W, 3 min,

re-sulting in decomposition) and standard activation with TFA or LiClO4failed(Scheme 14) [42]

Scheme 14 IEDAR of tetramethyl-4H-pyrazole (44) with 2,5-dihydrofurans 45 [42]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 19

Recently, the intriguing IEDA adducts 48 of

1-germa-2,3,4,5-tetraphenyl-1,1-dimethyl-2,4-cyclopentadiene (47) with N-methylmaleimide and maleic

anhydride were prepared by high-pressure reactions (Scheme 15) [43]

Scheme 15 IEDAR of 1-germa-2,3,4,5-tetraphenyl-1,1-dimethyl-2,4-cyclopentadiene (47)

[43]

Hetero IEDARs offer a useful protocol for construction of oxa- and cycles In particular, dihydropyrans are useful intermediates for a variety ofbiologically intriguing compounds Thus, many examples of high-pressuremediated IEDARs of dienes with dienophiles possessing carbonyl groups havebeen reported [9–14, 44, 45] One of the simplest approaches to sugars andsugar-like polyhydroxylated compounds from noncarbohydrate substrateswould be such hetero IEDARs A recent example of this type of reaction

aza-is an enantioselective high-pressure IEDAR of 1-methoxybuta-1,3-diene (49)

with tert-butyldimethylsilyloxyacetaldehyde (50) catalyzed by (salen)Co(II)

(53), (salen)Co(III)Cl (54), and (salen)Cr(III)Cl (55) complexes The

reac-tion afforded, in good yield (up to 90%) and with both high lectivity (up to 92%) and enantioselectivity (up to 94% ee), the hydrox-

diastereose-ymethyl(methoxy)tetrahydropyrans 51 and 52 (Scheme 16) [46].

Alternatively, the inverse electron-demand hetero IEDARs ofated carbonyl compounds with enol ethers serve as a short and attractiveroute to dihydropyrans For instance, the use of Lewis acids such as Eu(fod)3

α,β-unsatur-along with high-pressure afforded a high yield of the dihydropyran 56, as

shown in Scheme 17 [47] Analogous and more synthetically extensive resultsincluding dihydrothiopyrans were also reported [48–52]

The desperate search for effective anticancer and anti-HIV therapeuticagents has greatly stimulated research on specifically modified sugars Syn-

thesis of the dihydropyrans 59, incorporating annelated spirocyclopropane

moieties, has been accomplished by means of an inverse-demand hetero

IEDAR of methyl trans-4-benzyloxy-2-oxo-3-butenoate (57) onto benzyl

(cy-clopropylidenemethyl) ether (58) as the key step (Scheme 18) [53]

Fur-ther transformations led to 3-benzylatedα- and β-anomeric deoxy-(D,L)-arabino-hexopyranoside-2,1
-cyclopropanes 60.

benzylspiro[2]-Scheme 16 Enantioselective high-pressure IEDAR of 1-methoxybuta-1,3-diene (49)

with tert-butyldimethylsilyloxyacetaldehyde (50) catalyzed by (salen)Co(II) (53) and

(salen)Cr(III)Cl (55) complexes [46]

One of the simplest preparations of the pyridine skeleton would behetero IEDARs of nitriles with dienes, which would, however, be highlylimited because of the small number of activated dienes and nitriles The

hetero IEDARs of 2,3-dimethyl-1,3-butadiene (61) with itrile (62) at 0.15 GPa and 50◦C afforded 3,4-dimethyl-6-perfluoroheptyl-

perfluorooctanon-High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 21

Scheme 17 Hetero IEDAR of an α,β-unsaturated carbonyl compound with enol ether:

a highly efficient synthesis of the dihydropyran 56 [47]

Scheme 18 Synthesis of 3-benzylated α- and β-anomeric benzylspiro[2]-deoxy-( D , L

)-arabino-hexopyranoside-2,1
-cyclopropanes 60 via spirocyclopropane-annelated dropyrans 59 [53]

dihy-3,5-dihydropyridine (63), along with pyridine (64) though only in low yields, the former gradually eliminating hydrogen to give 64 (Scheme 19) [54] A higher pressure like 0.8 GPa might

3,4-dimethyl-6-perfluoroheptyl-3,5-highly improve the yields

Activated imines can also serve as dienophiles and the resulting adducts,piperidine-derived ring systems, constitute the skeleton of many naturallyoccurring alkaloids They exhibit a variety of biological activities and arefound in numerous therapeutic agents Thus, a short and efficient synthesis

of highly functionalized tetrahydropyridines is attained by high-pressure

aza-IEDAR, employing the imine 65 (Scheme 20) [55] The reaction was applied to

the stereoselective synthesis of a pipecolic acid derivative

Heterocyclic compounds which have, as a common structural feature,

a tetracyclic pyrido[2,3,4-kl]acridine system often offer striking

biolog-ical activities such as antitumor activities Specifically, a facile

synthe-sis of ascididemine (70) was achieved by high-pressure IEDAR of bromopyrido[2,3,4-kl]acridin-6-one (69) with propanal dimethylhydrazone

6H-4-(68), albeit in low yield of 21%, whereas 71 with 68 gave 72, an isomer of ascididemine (70) in moderate yield (Scheme 21) [56].

Scheme 19 Synthesis of pyridine 64 by hetero IEDAR of the diene 61 with nitrile 62 [54]

Scheme 20 Synthesis of tetrahydropyridines [55]

Scheme 21 A simple synthesis of ascididemine (70) via aza-IEDAR [56]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 23

2.2

Intramolecular Diels–Alder Reactions

In recent years, there has been considerable interest in synthetic applications

of intramolecular Diels–Alder reactions (IRDARs), because the ular reaction can offer some advantages over the intermolecular version,especially an increased reaction rate and higher selectivity IRDARs allow theregioselective and stereospecific introduction of multiple stereogenic centers.Therefore, these reactions have become a powerful method for the synthe-

intramolec-sis of polycyclic natural products Pressure effects of IRDARs of 73 were

investigated in comparison with sigmatropic reactions such as the Cope

re-arrangement of (Z)-1,3,5-hexatriene (75) (Scheme 22) [57, 58] It has been

proved that the –∆V= | values of the former are at least two times those of

the latter Importantly, large negative activation volumes ranging from – 24 to– 37 cm3mol–1, as well as large negative volume changes, have been found for

Scheme 22 Pressure effects on IRDARs of 73 and Cope reaction of 75 [57, 58]

this type of IRDAR In another example, the IRDAR of (Z)-1,3,8-nonatriene

(77) is highly favored over 1,5-hydrogen sigmatropy to 78 by applied pressure

(Scheme 23) [57, 58] At atmospheric pressure and 150◦C, the 1,5-hydrogen

shift predominated over the IRDAR in the yields, whereas even at 0.77 GPa,the ratio of the yields was completely reversed Thus, high pressure is ex-pected to be extremely fruitful in this type of IRDAR Indeed, a considerablenumber of high-pressure mediated IRDARs have already proved useful forconstruction of the skeleton of bioactive molecules [44, 45]

Sultams have been recognized to be useful for medicinal chemistry [59].The preparation of enantiomerically pureδ- and γ-sultams was achieved by

a high-pressure IRDAR As high as at 1.3 GPa, the sulfone 80 smoothly

un-derwent an IRDAR to give both slightly higher yield and asymmetric tion than under thermal conditions in refluxing toluene at ambient pressure

induc-The exo-sultam 81 predominated over the endo-sultam 82 by the chiral

(S)-1-phenylethyl substitution In contrast, the vinylsulfonamide 83, in which

double stereodifferentiation is anticipated by the presence of two stereogeniccenters, gave rise to a higher diastereoselectivity noted for the high-pressure

cycloaddition by virtue of both stereogenic elements present in 83 The

equa-torial disposition of the methyl group on the δ-sultam 84 dominated the stereochemical outcome of the reaction, the diastereoisomer 85 being formed

as the minor product (Scheme 24) [60]

Thermal or high-pressure induced IRDARs of the triene 86, featuring

ei-ther a sulfonate or sulfonamide moiety connecting a diene and a dienophile,

Scheme 23 Pressure effects on competitive IRDAR and 1,5-hydrogen shift of 77 [57, 58]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 25

Scheme 24 IRDARs of N-1-phenylethyl-substituted vinylsulfonamides 80 and 83 under

thermal and high-pressure conditions [60]

were found to proceed with moderate diastereoselectivity to give the

sul-tones 87 and 88 It is interesting to note that the ratio is reversed under high

pressure compared to thermal conditions Presumably, under high-pressure

conditions, the reaction takes place via a more compact endo-type transition

state (Scheme 25) [61] Similar IRDARs with high diastereoselectivity werealso reported [62]

Scheme 25 IRDARs of vinylsulfonate and vinylsulfonamide 86 [61]

Scheme 26 Synthetic approaches toward phorbols via the high-pressure mediated IRDARs

of furans 89 [64]

Scheme 27 Asymmetric IRDARs of furfuryl fumarates 91 under thermal and

high-pressure conditions [65]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 27

Scheme 28 Regioselective synthesis of pyridines via IRDARs of oximinomalonates 94 [68]

Tricyclic structures (A, B, and C rings) 90 possessing the functionality and

stereochemistry inherent in phorbol [63] and its analogues were constructed

in one step by a high-pressure IRDAR The nature of the 2-thioether stituent on the furan was critical for the success of the reaction; a range of

sub-high-pressure conditions with the phenylthiofuran 89 (R1= Me, R2= Ph) ledeither to the recovery of starting material or decomposition (Scheme 26) [64]

Asymmetric IRDARs of optically active furfuryl fumarates 91 were

investi-gated under thermal and high-pressure conditions The diastereoselectivitiesobserved increased with the size of the tether substituents, achieving up to86% in the case of R = t-Bu, though in the case of R = neo-Pen only 38% dewas obtained It is concluded the diastereoselectivity observed was thermo-dynamically controlled (Scheme 27) [65] An IRDA ring-expansion approachtoward taxinine (a carbocylic compound) [66] utilizing both Lewis acids andhigh pressure has been reported [67]

Finally, the thermal and high-pressure mediated IRDARs of an

oximino-malonate dienophile 94 tethered to a dienic carboxylic acid offer a facile method for regioselective synthesis of substituted pyridines 96 after aroma- tization of the adducts 95 with Cs2CO3(Scheme 28) [68]

2.3

1,3-Diploar Reactions

The 1,3-dipolar reaction (13DPR), whether concerted or not, undoubtedly vals Diels–Alder reactions in ubiquity as well as synthetic utility [69], andits synthetic potential is still far from being exhausted Both inter- and in-tramolecular 1,3-dipolar cycloadditions represent an efficient method for the

ri-syntheses of a wide variety of carbo- and heterocyclic compounds, includingnatural products.

The activation volume for 1,3-dipolar cycloaddition reactions is typicallyhighly negative (ca – 18 to – 32 cm3mol–1) In spite of the broad applicabil-ity of 1,3-dipolar cycloadditions in organic synthesis, high-pressure data arestill rare compared to Diels–Alder reactions Among other reasons, this ispartly due to the fact that the formation of 1,3-dipoles often involves a bond-breaking process and partly because, in certain cases, 1,3-dipoles are prone

to dimerization Classical examples of synthetic applications of high-pressure13DPRs have already been compiled [44]

The growing interest in the synthesis of aza-C-disaccharides is associated

with the search for new selective glycosidase inhibitors [70–72] One of thesimplest and most elegant approaches to this skeleton would be 13DPRs ofhydroxylated nitrones 13DPRs of the enantiomerically pure, hydroxylated

nitrones 97 and 100 to the glycols 98 and 101 are accelerated by applied pressure, giving the adducts 99 and 102, respectively (Scheme 29) In the reaction leading to the cyclic glycoside 102, the D-tartaric acid derived ni-

trone 100 is assumed to approach 101 from theα face (bottom) The oselectivity is apparently controlled by the 3-BnO substituent of the glycal

stere-as well stere-as by the t-BuO group next to the nitrone double bond Thus, the

process has proven to allow direct access to stereodifferentiated tricyclic

isoxazolidines like 102, which may serve as key intermediates to pseudo

aza-C-disaccharides [73]

Scheme 29 13DPRs of the enantiopure hydroxylated nitrones 97 and 100 with the glycals

98 and 101 [73]

High-Pressure Synthesis of Heterocycles Related to Bioactive Molecules 29Analogously, theL-valine derived nitrones 103 react with methyl acrylate (104) to produce the corresponding diastereomeric 3,5-disubstituted isoxa- zolines 105–108 In the case of the dibenzyl-substituted nitrones, in addition

to 3,5-disubstituted isoxazolines, the 3,4-disubstituted isoxazolines were alsoobtained in low yields High pressure just served to decrease the reaction

time The major products 105 were found to have the C-3/C-6 erythro and

C-3/C-5 trans relative configuration (Scheme 30) [74].

Scheme 30 13DPRs of L-valine derived nitrones 103 with methyl acrylate (104) [74]

The thermal and high-pressure 13DPRs of various Z- and E-nitrones, e.g.,

109 , with alkyl vinyl ethers, e.g., 110, catalyzed by a variety of chiral aborolidines, e.g., 113, were carried out with little success As exemplified in

oxaz-Scheme 31, conversion was achieved only up to 38% ee [75]

A putative type of 13DPRs, or otherwise formal [3 + 2] cycloadditions of

5-alkoxyoxazoles 114 with the carbonyl dipolarophile 115, were performed

either under high pressure or 0.1 MPa, catalyzed by tin(IV) chloride as trated in Scheme 32, the regiochemical results being generally complex [76].13DPRs of organic azides with alkenes and alkynes have long been known

illus-to give triazoles and a high-pressure mediated version of this reaction hasalso been well investigated [9–14, 44] A recent example is 13DPRs withmorpholino-1,3-butadienes and anα-ethynyl-enamine [77]

Finally, nonactivated nitriles do not usually undergo a 13DPR with a

1,3-dipole However, nitrones like 120–123 react with a variety of normal

ni-triles to afford the corresponding 2,3-dihydro-1,2,4-oxadiazoles in moderate